Potential effectiveness of a therapeutic HPV intervention campaign in Uganda.

Cervical cancer is a major source of morbidity and mortality in Uganda. In addition to prophylactic HPV vaccination, secondary prevention strategies are needed to reduce cancer burden. We evaluated the potential cancer reductions associated with a hypothetical single-contact therapeutic HPV intervention-with 70% coverage and variable efficacy [30%-100%]-using a three-stage HPV modeling framework reflecting HPV and cervical cancer burden in Uganda. In the reference case, we assumed prophylactic preadolescent HPV vaccination starting in 2020 with 70% coverage. A one-time therapeutic intervention targeting 35-year-old women in 2025 (not age-eligible for prophylactic vaccination) averted 1801 cervical cancers per 100 000 women over their lifetime (100% efficacy) or 533 cancers per 100 000 (30% efficacy). Benefits were considerably smaller in birth cohorts eligible for prophylactic HPV vaccination (768 cases averted per 100 000 at 100% efficacy). Evaluating the population-level impact over 40 years, we found introduction of a therapeutic intervention in 2025 with 100% efficacy targeted annually to 30-year-old women averted 139 000 incident cervical cancers in Uganda. This benefit was greatly reduced if efficacy was lower (30% efficacy; 41 000 cases averted), introduction was delayed (2040 introduction; 72 000 cases averted) or both (22 000 cases averted). We demonstrate the potential benefits of a single-contact HPV therapeutic intervention in a low-income setting, but show the importance of high therapeutic efficacy and early introduction timing relative to existing prophylactic programs. Reduced benefits from a less efficacious intervention may be somewhat offset if available within a shorter time frame.

Different human papillomavirus types share early natural history transitions in immunocompetent women.

Necessary stages of cervical carcinogenesis include acquisition of a carcinogenic human papillomavirus (HPV) type, persistence associated with the development of precancerous lesions, and invasion. Using prospective data from immunocompetent women in the Guanacaste HPV Natural History Study (NHS), the ASCUS-LSIL Triage Study (ALTS) and the Costa Rica HPV Vaccine Trial (CVT), we compared the early natural history of HPV types to inform transition probabilities for health decision models. We excluded women with evidence of high-grade cervical abnormalities at any point during follow-up and restricted the analysis to incident infections in all women and prevalent infections in young women (aged <30 years). We used survival approaches accounting for interval-censoring to estimate the time to clearance distribution for 20 529 HPV infections (64% were incident and 51% were carcinogenic). Time to clearance was similar across HPV types and risk classes (HPV16, HPV18/45, HPV31/33/35/52/58, HPV 39/51/56/59 and noncarcinogenic HPV types); and by age group (18-29, 30-44 and 45-54 years), among carcinogenic and noncarcinogenic infections. Similar time to clearance across HPV types suggests that relative prevalence can predict relative incidence. We confirmed that there was a uniform linear association between incident and prevalent infections for all HPV types within each study cohort. In the absence of progression to precancer, we observed similar time to clearance for incident infections across HPV types and risk classes. A singular clearance function for incident HPV infections has important implications for the refinement of microsimulation models used to evaluate the cost-effectiveness of novel prevention technologies.

The development of "automated visual evaluation" for cervical cancer screening: The promise and challenges in adapting deep-learning for clinical testing: Interdisciplinary principles of automated visual evaluation in cervical screening.

There is limited access to effective cervical cancer screening programs in many resource-limited settings, resulting in continued high cervical cancer burden. Human papillomavirus (HPV) testing is increasingly recognized to be the preferable primary screening approach if affordable due to superior long-term reassurance when negative and adaptability to self-sampling. Visual inspection with acetic acid (VIA) is an inexpensive but subjective and inaccurate method widely used in resource-limited settings, either for primary screening or for triage of HPV-positive individuals. A deep learning (DL)-based automated visual evaluation (AVE) of cervical images has been developed to help improve the accuracy and reproducibility of VIA as assistive technology. However, like any new clinical technology, rigorous evaluation and proof of clinical effectiveness are required before AVE is implemented widely. In the current article, we outline essential clinical and technical considerations involved in building a validated DL-based AVE tool for broad use as a clinical test.

Choosing the optimal HPV vaccine: The health impact and economic value of the nonavalent and bivalent HPV vaccines in 48 Gavi-eligible countries.

The human papillomavirus (HPV) vaccines may provide some level of cross-protection against high-risk HPV genotypes not directly targeted by the vaccines. We evaluated the long-term health and economic impacts of routine HPV vaccination using either the nonavalent HPV vaccine or the bivalent HPV vaccine in the context of 48 Gavi-eligible countries. We used a multi-modeling approach to compare the bivalent with or without cross-protection and the nonavalent HPV vaccine. The optimal, that is, most cost-effective, vaccine was the vaccine with an incremental cost-effectiveness ratio below the per-capita gross domestic product (GDP) for each country. By 2100 and assuming 70% HPV vaccination coverage, a bivalent vaccine without cross-protection, a bivalent vaccine with favorable cross-protection and the nonavalent vaccine were projected to avert 14.9, 17.2 and 18.5 million cumulative cases of cervical cancer across all 48 Gavi-eligible countries, respectively. The relative value of the bivalent vaccine compared to the nonavalent vaccine increased assuming a bivalent vaccine conferred high cross-protection. For example, assuming a cost-effectiveness threshold of per-capita GDP, the nonavalent vaccine was optimal in 83% (n = 40) of countries if the bivalent vaccine did not confer cross-protection; however, the proportion of countries decreased to 63% (n = 30) if the bivalent vaccine conferred high cross-protection. For lower cost-effectiveness thresholds, the bivalent vaccine was optimal in a greater proportion of countries, under both cross-protection assumptions. Although the nonavalent vaccine is projected to avert more cases of cervical cancer, the bivalent vaccine with favorable cross-protection can prevent a considerable number of cases and would be considered a high-value vaccine for many Gavi-eligible countries.

Given a choice between self-sampling at home for HPV testing and standard of care screening at the clinic, what do African American women choose? Findings from a group randomized controlled trial.

The goals of this study were to: (1) evaluate adherence to cervical cancer screening using a patient-centered approach that provided a choice of self-sampling at home for human papillomavirus (HPV) testing or standard of care screening at the local health department ('Choice') versus only standard of care screening at the local health department ('SCS') among un/under-screened African-American women; and (2) examine whether women given a choice were more likely to choose and adhere to self-sampling for HPV testing. We conducted a group randomized trial among un/under-screened African-American women in the Mississippi Delta, with "town" as the unit of randomization (12 towns). Both interventions (i.e., 'Choice' versus 'SCS') were delivered by Community Health Workers (CHWs) through a door-to-door approach. A total of 335 women were enrolled in the study from 2016 to 2019. The 'Choice' arm had a significantly (p = 0.005) higher adherence to screening compared to the 'SCS' arm after adjusting for the cluster effect and other relevant behavioral variables. Participants in the 'Choice' arm were 5.62 (95% CI 1.71-18.44) times more likely to adhere to cervical cancer screening compared to participants in the 'SCS' arm. Women in the 'Choice' arm were significantly more likely to choose (76%) and adhere to self-sampling at home for HPV testing (48% adherence) compared to standard of care screening at the local health department (7.5% adherence). A theory-driven, CHW-led intervention can effectively promote cervical cancer screening among un/under-screened African-American women in a rural setting when women are provided with a choice between two screening modalities. Clinical Trials Registration: NCT03713710.

A proposed new generation of evidence-based microsimulation models to inform global control of cervical cancer.

Health decision models are the only available tools designed to consider the lifetime natural history of human papillomavirus (HPV) infection and pathogenesis of cervical cancer, and the estimated long-term impact of preventive interventions. Yet health decision modeling results are often considered a lesser form of scientific evidence due to the inherent needs to rely on imperfect data and make numerous assumptions and extrapolations regarding complex processes. We propose a new health decision modeling framework that de-emphasizes cytologic-colposcopic-histologic diagnoses due to their subjectivity and lack of reproducibility, relying instead on HPV type and duration of infection as the major determinants of subsequent transition probabilities. We posit that the new model health states (normal, carcinogenic HPV infection, precancer, cancer) and corollary transitions are universal, but that the probabilities of transitioning between states may vary by population. Evidence for this variability in host response to HPV infections can be inferred from HPV prevalence patterns in different regions across the lifespan, and might be linked to different average population levels of immunologic control of HPV infections. By prioritizing direct estimation of model transition probabilities from longitudinal data (and limiting reliance on model-fitting techniques that may propagate error when applied to multiple transitions), we aim to reduce the number of assumptions for greater transparency and reliability. We propose this new microsimulation model for critique and discussion, hoping to contribute to models that maximally inform efficient strategies towards global cervical cancer elimination.

The cost-effectiveness of human papillomavirus self-collection among cervical cancer screening non-attenders in El Salvador.

Cervical cancer screening with human papillomavirus (HPV) DNA testing has been incorporated into El Salvador's national guidelines. The feasibility of home-based HPV self-collection among women who do not attend screening at the clinic (i.e., non-attenders) has been demonstrated, but cost-effectiveness has not been evaluated. Using cost and compliance data from El Salvador, we informed a mathematical microsimulation model of HPV infection and cervical carcinogenesis to conduct a cost-effectiveness analysis from the societal perspective. We estimated the reduction in cervical cancer risk, lifetime cost per woman (2017 US$), life expectancy, and incremental cost-effectiveness ratio (ICER, 2017 US$ per year of life saved [YLS]) of a program with home-based self-collection of HPV (facilitated by health promoters) for the 18% of women reluctant to screen at the clinic. The model was calibrated to epidemiologic data from El Salvador. We evaluated health and economic outcomes of the self-collection intervention for women aged 30 to 59 years, alone and in concert with clinic-based HPV provider-collection. Home-based self-collection of HPV was projected to reduce population cervical cancer risk by 14% and cost $1210 per YLS compared to no screening. An integrated program reaching 99% coverage with both provider- and home-based self-collection of HPV reduced cancer risk by 74% (compared to no screening), and cost $1210 per YLS compared to provider-collection alone. Self-collection facilitated by health promoters is a cost-effective strategy for increasing screening uptake in El Salvador.

Health impact of delayed implementation of cervical cancer screening programs in India: A modeling analysis.

India has the highest burden of cervical cancer in the world. To estimate the consequences of delaying implementation of organized cervical cancer screening, we projected the avertable burden of disease under different implementation scenarios of a screening program. We used an individual-based microsimulation model of human papillomavirus (HPV) infection and cervical cancer calibrated to epidemiologic data from India to project age-specific cancer incidence and mortality reductions associated with screening (once-in-a-lifetime among women aged 30-34 years) with one-visit visual inspection with acetic acid (VIA) and one- and two-visit HPV DNA testing. We then applied these reductions to a population model to project the lifetime cervical cancer cases and deaths averted under different implementation scenarios taking place from 2017 to 2026: (1) immediate implementation of screening with currently available screening tests (one-visit VIA, two-visit HPV testing); (2) immediate implementation of screening with currently available screening tests, with a switch to point-of-care one-visit HPV testing in 5 years; and (3) 5-year delayed implementation of screening with current screening tests or point-of-care HPV testing. Immediate implementation of two-visit HPV testing with a switch to one-visit HPV testing averted 574,100 cases and 382,500 deaths over the lifetimes of 81.4 million 30- to 34-year-old women screened once between 2017 and 2026. Delayed implementation with a one-visit HPV test averted 209,300 cases and 139,100 deaths. Delaying implementation of screening programs in high-burden settings will result in substantial morbidity and mortality among women beyond the age for adolescent HPV vaccination.

Inefficiencies of over-screening and under-screening for cervical cancer prevention in the U.S.

There is limited information on the cost-inefficiencies of non-adherence to recommended cervical cancer screening or the potential value for improving non-adherence. We estimated the incremental value of adhering to recommended screening every three years with cytology, using a disease simulation model that integrated real-world screening practice data from New Mexico. The amount that can be spent to improve adherence was estimated by calculating the incremental net monetary benefit (INMB) under scenarios of Current Practice (assuming a population of mixed adherence) and Uniformly Non-Adherent populations with imperfect or perfect adherence to follow-up of screen-positive women. Getting unscreened women screened every three years by cytology was a better value than increasing screening in the under-screened or reducing screening in the over-screened. For example, INMBs were $3998 for screening previously unscreened women versus $136 for eliminating annual screening at a willingness-to-pay threshold of $100,000 per quality-adjusted life-year gained. Strategies to reach unscreened women are potentially high-value investments.

To expand coverage, or increase frequency: Quantifying the tradeoffs between equity and efficiency facing cervical cancer screening programs in low-resource settings.

Cervical cancer is a leading cause of cancer death worldwide, with 85% of the disease burden residing in less developed regions. To inform evidence-based decision-making as cervical cancer screening programs are planned, implemented, and scaled in low- and middle-income countries, we used cost and test performance data from the START-UP demonstration project in Uganda and a microsimulation model of HPV infection and cervical carcinogenesis to quantify the health benefits, distributional equity, cost-effectiveness, and financial impact of either (1) improving access to cervical cancer screening or (2) increasing the number of lifetime screening opportunities for women who already have access. We found that when baseline screening coverage was low (i.e., 30%), expanding coverage of screening once in a lifetime to 50% can yield comparable reductions in cancer risk to screening two or three times in a lifetime at 30% coverage, lead to greater reductions in health disparities, and cost 150 international dollars (I$) per year of life saved (YLS). At higher baseline screening coverage levels (i.e., 70%), screening three times in a lifetime yielded greater health benefits than expanding screening once in a lifetime to 90% coverage, and would have a cost-effectiveness ratio (I$590 per YLS) below Uganda's per capita GDP. Given very low baseline coverage at present, we conclude that a policy focus on increasing access for previously unscreened women appears to be more compatible with improving both equity and efficiency than a focus on increasing frequency for a small subset of women.

Cost-effectiveness of cervical cancer screening methods in low- and middle-income countries: A systematic review.

The incidence of cervical cancer in low- and middle-income countries (LMICs) is five times higher than that observed in high-income countries (HICs). This discrepancy is largely attributed to the implementation of cytology-based screening programmes in HICs. However, due to reduced health system infrastructure requirements, HPV testing (self- and provider-collected) and visual inspection with acetic acid (VIA) have been proposed as alternatives that may be better suited to LMICs. Knowing the relative value of different screening options can inform policy and the development of sustainable prevention programs. We searched MEDLINE and EMBASE for English language publications detailing model-based cost-effectiveness analyses of cervical cancer screening methods in LMICs from 2000 to 2016. The main outcome of interest was the incremental cost-effectiveness ratio (ICER). Quantitative data were extracted to compare commonly evaluated screening methods and a descriptive review was conducted for each included study. Of the initial 152 articles reviewed, 19 met inclusion criteria. Generally, cytology-based screening was shown to be the least effective and most costly screening method. Whether provider-collected HPV testing or VIA was the more efficient alternative depended on the cost of the HPV test, loss to follow-up and VIA test performance. Self-collected HPV testing was cost-effective when it yielded population coverage gains over other screening methods. We conclude that HPV testing and VIA are more cost-effective screening methods than cytology in LMICs. Policy makers should consider HPV testing with self-collection of samples if it yields gains in population coverage.

Estimating the value of point-of-care HPV testing in three low- and middle-income countries: a modeling study.

BACKGROUND: Where resources are available, the World Health Organization recommends cervical cancer screening with human papillomavirus (HPV) DNA testing and subsequent treatment of HPV-positive women with timely cryotherapy. Newer technologies may facilitate a same-day screen-and-treat approach, but these testing systems are generally too expensive for widespread use in low-resource settings. METHODS: To assess the value of a hypothetical point-of-care HPV test, we used a mathematical simulation model of the natural history of HPV and data from the START-UP multi-site demonstration project to estimate the health benefits and costs associated with a shift from a 2-visit approach (requiring a return visit for treatment) to 1-visit HPV testing (i.e., screen-and-treat). We estimated the incremental net monetary benefit (INMB), which represents the maximum additional lifetime cost per woman that could be incurred for a new point-of-care HPV test to be cost-effective, depending on expected loss to follow-up between visits (LTFU) in a given setting. RESULTS: For screening three times in a lifetime at 100% coverage of the target population, when LTFU was 10%, the INMB of the 1-visit relative to the 2-visit approach was I$13 in India, I$36 in Nicaragua, and I$17 in Uganda. If LTFU was 30% or greater, the INMB values for the 1-visit approach in all countries was equivalent to or exceeded total lifetime costs associated with screening three times in a lifetime. At a LTFU level of 70%, the INMB of the 1-visit approach was I$127 in India, I$399 in Nicaragua, and I$121 in Uganda. CONCLUSIONS: These findings indicate that point-of-care technology for cervical cancer screening may be worthy of high investment if linkage to treatment can be assured, particularly in settings where LTFU is high.

Inefficiencies and High-Value Improvements in U.S. Cervical Cancer Screening Practice: A Cost-Effectiveness Analysis.

BACKGROUND: Studies suggest that cervical cancer screening practice in the United States is inefficient. The cost and health implications of nonadherence in the screening process compared with recommended guidelines are uncertain. OBJECTIVE: To estimate the benefits, costs, and cost-effectiveness of current cervical cancer screening practice and assess the value of screening improvements. DESIGN: Model-based cost-effectiveness analysis. DATA SOURCES: New Mexico HPV Pap Registry; medical literature. TARGET POPULATION: Cohort of women eligible for routine screening. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTION: Current cervical cancer screening practice; improved adherence to guidelines-based screening interval, triage testing, diagnostic referrals, and precancer treatment referrals. OUTCOME MEASURES: Reductions in lifetime cervical cancer risk, quality-adjusted life-years (QALYs), lifetime costs, incremental cost-effectiveness ratios, and incremental net monetary benefits (INMBs). RESULTS OF BASE-CASE ANALYSIS: Current screening practice was associated with lower health benefit and was not cost-effective relative to guidelines-based strategies. Improvements in the screening process were associated with higher QALYs and small changes in costs. Perfect adherence to screening every 3 years with cytologic testing and adherence to colposcopy/biopsy referrals were associated with the highest INMBs ($759 and $741, respectively, at a willingness-to-pay threshold of $100,000 per QALY gained); together, the INMB increased to $1645. RESULTS OF SENSITIVITY ANALYSIS: Current screening practice was inefficient in 100% of simulations. The rank ordering of screening improvements according to INMBs was stable over a range of screening inputs and willingness-to-pay thresholds. LIMITATION: The effect of human papillomavirus vaccination was not considered. CONCLUSIONS: The added health benefit of improving adherence to guidelines, especially the 3-year interval for cytologic screening and diagnostic follow-up, may justify additional investments in interventions to improve U.S. cervical cancer screening practice. PRIMARY FUNDING SOURCE: U.S. National Cancer Institute.

Cervical cancer screening in low-resource settings: A cost-effectiveness framework for valuing tradeoffs between test performance and program coverage.

As cervical cancer screening programs are implemented in low-resource settings, protocols are needed to maximize health benefits under operational constraints. Our objective was to develop a framework for examining health and economic tradeoffs between screening test sensitivity, population coverage and follow-up of screen-positive women, to help decision makers identify where program investments yield the greatest value. As an illustrative example, we used an individual-based Monte Carlo simulation model of the natural history of human papillomavirus (HPV) and cervical cancer calibrated to epidemiologic data from Uganda. We assumed once in a lifetime screening at age 35 with two-visit HPV DNA testing or one-visit visual inspection with acetic acid (VIA). We assessed the health and economic tradeoffs that arise between (i) test sensitivity and screening coverage; (ii) test sensitivity and loss to follow-up (LTFU) of screen-positive women; and (iii) test sensitivity, screening coverage and LTFU simultaneously. The decline in health benefits associated with sacrificing HPV DNA test sensitivity by 20% (e.g., shifting from provider- to self-collection of specimens) could be offset by gains in coverage if coverage increased by at least 20%. When LTFU was 10%, two-visit HPV DNA testing with 80-90% sensitivity was more effective and more cost-effective than one-visit VIA with 40% sensitivity and yielded greater health benefits than VIA even as VIA sensitivity increased to 60% and HPV test sensitivity declined to 70%. As LTFU increased, two-visit HPV DNA testing became more costly and less effective than one-visit VIA. Setting-specific data on achievable test sensitivity, coverage, follow-up rates and programmatic costs are needed to guide decision making for cervical cancer screening.

The comparative and cost-effectiveness of HPV-based cervical cancer screening algorithms in El Salvador.

Cervical cancer is the leading cause of cancer death among women in El Salvador. Utilizing data from the Cervical Cancer Prevention in El Salvador (CAPE) demonstration project, we assessed the health and economic impact of HPV-based screening and two different algorithms for the management of women who test HPV-positive, relative to existing Pap-based screening. We calibrated a mathematical model of cervical cancer to epidemiologic data from El Salvador and compared three screening algorithms for women aged 30-65 years: (i) HPV screening every 5 years followed by referral to colposcopy for HPV-positive women (Colposcopy Management [CM]); (ii) HPV screening every 5 years followed by treatment with cryotherapy for eligible HPV-positive women (Screen and Treat [ST]); and (iii) Pap screening every 2 years followed by referral to colposcopy for Pap-positive women (Pap). Potential harms and complications associated with overtreatment were not assessed. Under base case assumptions of 65% screening coverage, HPV-based screening was more effective than Pap, reducing cancer risk by ∼ 60% (Pap: 50%). ST was the least costly strategy, and cost $2,040 per year of life saved. ST remained the most attractive strategy as visit compliance, costs, coverage, and test performance were varied. We conclude that a screen-and-treat algorithm within an HPV-based screening program is very cost-effective in El Salvador, with a cost-effectiveness ratio below per capita GDP.

An updated natural history model of cervical cancer: derivation of model parameters.

Mathematical models of cervical cancer have been widely used to evaluate the comparative effectiveness and cost-effectiveness of preventive strategies. Major advances in the understanding of cervical carcinogenesis motivate the creation of a new disease paradigm in such models. To keep pace with the most recent evidence, we updated a previously developed microsimulation model of human papillomavirus (HPV) infection and cervical cancer to reflect 1) a shift towards health states based on HPV rather than poorly reproducible histological diagnoses and 2) HPV clearance and progression to precancer as a function of infection duration and genotype, as derived from the control arm of the Costa Rica Vaccine Trial (2004-2010). The model was calibrated leveraging empirical data from the New Mexico Surveillance, Epidemiology, and End Results Registry (1980-1999) and a state-of-the-art cervical cancer screening registry in New Mexico (2007-2009). The calibrated model had good correspondence with data on genotype- and age-specific HPV prevalence, genotype frequency in precancer and cancer, and age-specific cancer incidence. We present this model in response to a call for new natural history models of cervical cancer intended for decision analysis and economic evaluation at a time when global cervical cancer prevention policy continues to evolve and evidence of the long-term health effects of cervical interventions remains critical.

Adapting a model of cervical carcinogenesis to self-identified Black women to evaluate racial disparities in the United States.

BACKGROUND: Self-identified Black women in the United States have higher cervical cancer incidence and mortality than the general population, but these differences have not been clearly attributed across described cancer care inequities. METHODS: A previously established microsimulation model of cervical cancer was adapted to reflect demographic, screening, and survival data for Black US women and compared with a model reflecting data for all US women. Each model input with stratified data (all-cause mortality, hysterectomy rates, screening frequency, screening modality, follow-up, and cancer survival) was sequentially replaced with Black-race specific data to arrive at a fully specified model reflecting Black women. At each step, we estimated the relative contribution of inputs to observed disparities. RESULTS: Estimated (hysterectomy-adjusted) cervical cancer incidence was 8.6 per 100 000 in the all-race model vs 10.8 per 100 000 in the Black-race model (relative risk [RR] = 1.24, range = 1.23-1.27). Estimated all-race cervical cancer mortality was 2.9 per 100 000 vs 5.5 per 100 000 in the Black-race model (RR = 1.92, range = 1.85-2.00). We found the largest contributors of incidence disparities were follow-up from positive screening results (47.3% of the total disparity) and screening frequency (32.7%). For mortality disparities, the largest contributor was cancer survival differences (70.1%) followed by screening follow-up (12.7%). CONCLUSION: To reduce disparities in cervical cancer incidence and mortality, it is important to understand and address differences in care access and quality across the continuum of care. Focusing on the practices and policies that drive differences in treatment and follow-up from cervical abnormalities may have the highest impact.

Opportunities for Achieving the Cancer Moonshot Goal of a 50% Reduction in Cancer Mortality by 2047.

On February 2, 2022, President Biden and First Lady Dr. Biden reignited the Cancer Moonshot, setting a new goal to reduce age-standardized cancer mortality rates by at least 50% over the next 25 years in the United States. We estimated trends in U.S. cancer mortality during 2000 to 2019 for all cancers and the six leading types (lung, colorectum, pancreas, breast, prostate, liver). Cancer death rates overall declined by 1.4% per year from 2000 to 2015, accelerating to 2.3% per year during 2016 to 2019, driven by strong declines in lung cancer mortality (-4.7%/year, 2014 to 2019). Recent declines in colorectal (-2.0%/year, 2010-2019) and breast cancer death rates (-1.2%/year, 2013-2019) also contributed. However, trends for other cancer types were less promising. To achieve the Moonshot goal, progress against lung, colorectal, and breast cancer deaths needs to be maintained and/or accelerated, and new strategies for prostate, liver, pancreatic, and other cancers are needed. We reviewed opportunities to prevent, detect, and treat these common cancers that could further reduce population-level cancer death rates and also reduce disparities. SIGNIFICANCE: We reviewed opportunities to prevent, detect, and treat common cancers, and show that to achieve the Moonshot goal, progress against lung, colorectal, and breast cancer deaths needs to be maintained and/or accelerated, and new strategies for prostate, liver, pancreatic, and other cancers are needed. See related commentary by Bertagnolli et al., p. 1049. This article is highlighted in the In This Issue feature, p. 1027.

Estimating human papillomavirus vaccine efficacy from a single-arm trial: proof-of-principle in the Costa Rica Vaccine Trial.

BACKGROUND: The World Health Organization recommends a 1- or 2-dose human papillomavirus (HPV) vaccination schedule for females aged 9 to 20 years. Studies confirming the efficacy of a single dose and vaccine modifications are needed, but randomized controlled trials are costly and face logistical and ethical challenges. We propose a resource-efficient single-arm trial design that uses untargeted and unaffected HPV types as controls. METHODS: We estimated HPV vaccine efficacy (VE) from a single arm by comparing 2 ratios: the ratio of the rate of persistent incident infection with vaccine-targeted HPV 16 and 18 (HPV 16/18) and cross-protected types HPV 31, 33, and 45 (HPV 31/33/45) to vaccine-unaffected types HPV 35, 39, 51, 52, 56, 58, 59, and 66 (HPV 35/39/51/52/56/58/59/66) vs the ratio of prevalence of these types at the time of trial enrollment. We compare VE estimates using only data from the bivalent HPV 16/18 vaccine arm of the Costa Rica Vaccine Trial with published VE estimates that used both the vaccine and control arms. RESULTS: Our single-arm approach among 3727 women yielded VE estimates against persistent HPV 16/18 infections similar to published 2-arm estimates from the trial (according-to-protocol cohort: 91.0% , 95% CI = 82.9% to 95.3% [single-arm] vs 90.9% , 95% CI = 82.0% to 95.9% [2-arm]; intention-to-treat cohort: 41.7%, 95% CI = 32.4% to 49.8% [single-arm] vs 49.0% , 95% CI = 38.1% to 58.1% [2-arm]). VE estimates were also similar in analytic subgroups (number of doses received; baseline HPV serology status). CONCLUSIONS: We demonstrate that a single-arm design yields valid VE estimates with similar precision to a randomized controlled trial. Single-arm studies can reduce the sample size and costs of future HPV vaccine trials while avoiding concerns related to unvaccinated control groups. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00128661.

Upper age limits for US male human papillomavirus vaccination for oropharyngeal cancer prevention: a microsimulation-based modeling study.

BACKGROUND: Human papillomavirus (HVP)-positive oropharyngeal cancer is the most common HPV-associated cancer in the United States. The age at acquisition of oral HPV infections that cause oropharyngeal cancer (causal infections) is unknown; consequently, the benefit of vaccination of US men aged 27-45 years remains uncertain. METHODS: We developed a microsimulation-based, individual-level, state-transition model of oral HPV16 and HPV16-positive oropharyngeal cancer among heterosexual US men aged 15-84 years, calibrated to population-level data. We estimated the benefit of vaccination of men aged 27-45 years for prevention of oropharyngeal cancer, accounting for direct- and indirect effects (ie, herd effects) of male and female vaccination. RESULTS: In the absence of vaccination, most (70%) causal oral HPV16 infections are acquired by age 26 years, and 29% are acquired between ages 27 and 45 years. Among men aged 15-45 years in 2021 (1976-2006 birth cohorts), status quo vaccination of men through age 26 years is estimated to prevent 95% of 153 450 vaccine-preventable cancers. Assuming 100% vaccination in 2021, extending the upper age limit to 30, 35, 40, or 45 years for men aged 27-45 years (1976-1994 cohorts) is estimated to yield small benefits (3.0%, 4.2%, 5.1%, and 5.6% additional cancers prevented, respectively). Importantly, status quo vaccination of men through age 26 years is predicted to result in notable declines in HPV16-positive oropharyngeal cancer incidence in young men by 2035 (51% and 24% declines at ages 40-44 years and 45-49 years, respectively) and noticeable declines (12%) overall by 2045. CONCLUSION: Most causal oral HPV16 infections in US men are acquired by age 26 years, underscoring limited benefit from vaccination of men aged 27-45 years for prevention of HPV16-positive oropharyngeal cancers.